TM6SF2 (transmembrane 6 superfamily member 2) is a key regulator of hepatic lipid metabolism with significant implications for liver disease. The protein functions primarily in liver fat metabolism by influencing triglyceride secretion and hepatic lipid droplet content 1. TM6SF2 operates through multiple mechanisms, including direct interaction with PNPLA3 to facilitate polyunsaturated fatty acid transfer from triglycerides to phosphatidylcholine, which is crucial for maintaining proper lipid composition and membrane fluidity 2. The protein also regulates antitumor immunity by directly binding to IKKβ and inhibiting NF-κB signaling, thereby reducing IL-6 secretion and activating cytotoxic CD8+ T cells 3. Additionally, intestinal TM6SF2 maintains gut barrier function and prevents microbial dysbiosis through interactions with fatty acid-binding protein 5 4. Clinically, TM6SF2 genetic variants, particularly the E167K polymorphism, are strongly associated with non-alcoholic fatty liver disease (NAFLD) susceptibility and progression 56. Individuals carrying risk variants show increased susceptibility to hepatic steatosis, steatohepatitis, and hepatocellular carcinoma 7. The E167K variant specifically impairs PUFA transfer mechanisms, promoting hepatic steatosis and injury, making TM6SF2 a potential therapeutic target for metabolic liver diseases 2.